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Rosenfeld: Failure of anti-PDGF trials due to study design flaws
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KOLOA, Hawaii — Philip J. Rosenfeld, MD, PhD, had a caution for colleagues at Retina 2017 here: The cardinal rule of phase 3 clinical trial design is to not change what appears to work in phase 2.
Rosenfeld, whose presentation garnered him Speaker of the Day honors, talked about the recent failures of two anti-PDGF agent trials, one for pegpleranib (Fovista, Ophthotech) in combination with ranibizumab (Lucentis, Genentech), and one for rinucumab combined with aflibercept (Eylea), both Regeneron, for the treatment of neovascular age-related macular degeneration.
Philip J. Rosenfeld
“There are two reasons why these studies didn’t work. Either it’s a viable treatment and the clinical trial designs were seriously flawed, or it’s a failed therapeutic strategy,” he said.
Concentrating on the failed pegpleranib trial, Rosenfeld pointed to flawed data reporting carrying over from each phase of the trials. For example, patients included in the phase 2 trial had only classic-containing lesions, whereas [subretinal hyperreflective material, SHRM]-containing lesions were included in phase 3 and was looked at in a retrospective subgroup analysis.
“In my experience, designing a prospective trial based on subgroup retrospective analyses has never worked for anything substantive,” he said.
Lesion inclusion criteria was changed from fluorescein angiography-based criteria to OCT-based criteria, and there was a lesion size imbalance at baseline in the phase 2 study that could have rendered phase 2 results misleading.
“They failed to perform multivariate analysis. Any clinical trialist will tell you that you have to adjust for imbalances at baseline before you can make any statement about the clinical trial results,” he said.
Rosenfeld said the phase 3 trial failed because, “They designed what they thought was a successful phase 2 and then they changed the entry criteria to go to the phase 3. Never do that. You can’t change what you think worked and hope that works in the phase 3,” he said. “They gambled on 1,800 patients, and they failed.” – by Patricia Nale, ELS
Reference:
Rosenfeld PJ. Anti-PDGF and age-related macular degeneration treatment: Where do we stand? Presented at: Retina 2017; Jan. 16-20, 2017; Koloa, Hawaii.
Disclosure: Rosenfeld is a consultant for Alcon, Chengdu Kanghong Biotech, Genentech, Regeneron and Tyrogenex.